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denosumab osteonecrosis of
the mandible: a new entity?
a case report.
J Craniomaxillofac Surg. 2013 jun;41(4):e65-9.
aBstract
5
introduction
In the treatment of osteoporosis multiple myeloma and bone metastases from prostate and breast cancer bisphosphonates play a major role. Bisphosphonates, particularly the use of intra-venous bisphosphonates, reduce bone resorption by inhibiting osteoclast function, thereby re-ducing pain1,2 and correcting hypercalcemia3,4. However, not all patients respond well to
bisphos-phonate treatment and even in those who do respond well, there is increasing awareness and reporting of the adverse effects of these drugs in the literature5. Many of these reports relate to
concerns regarding gastrointestinal complaints, but more frequently 0,01%-9,1% osteonecrosis of the jaw is being recognised and reported6. This is a serious condition which can lead to loss of
part if not all of the jaw even in the face of best known treatment. Intravenous use of bisphos-phonates are limited in dosage because of their renal toxicity7. In addition bisphosphonates
have a long half-life and once incorporated into the bone, remains effective for several years after intake. In the search for a better solution a new drug, Denosumab (Prolia, Xgeva: Amgen Europe), a fully human monoclonal antibody targeted to Receptor Activator of Nuclear Factor kB Ligand (RANKL), has recently been developed. RANKL has been found to act as the primary signal for bone removal8-16. Denosumab is more effective in inhibiting osteoclasts in comparison
to bisphosphonates. Because there is no binding to bone, it potentially will reduce the long term effects associated with bone incorporation. Denosumab’s binding to RANKL theoretically will produce a more physiologic action with hence fewer side effects. Its main indications for use are stated to be osteoporosis and bone metastases with the drug having recently been granted approval by the FDA for these indications.
There have been several publications on Denosumab, most reports investigate the effect of denosumab when compared to the effect of bisphosphonates. To our knowledge adverse effects of denosumab on the mandible or maxilla have received relatively little attention12,17,18.
Osteone-crosis of the jaw may still be one of these adverse effects of denosumab, with the incidence of osteonecrosis of the jaw ranging from 0.9% to 5%12,14,16.
We present a case of osteonecrosis of the jaw following denosumab treatment.
case rePort
In October 2007 he was enrolled into a phase III randomized double blind multicentre trial, testing the efficacy of denosumab with zoledronic acid in the treatment of bone metastases of hormone resistant prostate cancer.
In May 2008 a dehiscence of the oral mucosa developed in the lower left quadrant without sequestration of the underlying bone. In February 2009 he was admitted with swelling of the floor of mouth and tongue of infectious origin, this was treated with surgical drainage and an-timicrobials amoxicillin and clavulanic acid (Augmentin). Because of ongoing symptoms he was referred to the Leiden University Medical Center in May 2009.
At presentation intra and extra-oral swelling and an area of brown-colored exposed bone was present in region 34 to 36 (figure 1A), The submandibular swelling later developed into an abscess with fistula. A panoramic radiograph and CT-scan showed sclerosis and lysis in the left mandible (region 33-35) and subperiosteal bone formation (figure 1B+C). Cultures showed
Figure 1 Intra-oral and radiological situation at first presentation in LUMC May 2009
a. intra-oral view: exposed bone.
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mixed flora although Actinomyces was not found. The patient was treated by drainage of theabscess and antibiotics for four weeks.
Because of persisting symptoms a sequestrectomy was performed under general anaesthe-sia with removal of the remaining dentition from the clinically sclerotic bone. The lingual cortex and alveolar process particularly in region 34 to 36 appeared non-vital; bone was lowered and removed (figure 2A+C) until bleeding, relatively viable bone remained. The wounds were primar-ily closed in a multi-layer technique5.
One fistula produced yellow grains, and new cultures at the time of surgery grew Actinomy-cosis. Penicillin and metronidazole were administered for five days intravenously followed by an eight week oral regime. Histologic examination of the bone showed necrotic bone and areas of extensive remodelling. A mixed-cell infiltrate and Actinomycosis were seen; there were no signs of metastases of the prostate cancer.
Figure 2 First surgery: intra-operative view of third quadrant
The research group organizing the phase III trial was asked to code break and reveal the drug given to the patient; it was Denosumab. Twice a year he received a subcutaneous injection with a dose of 60 mg Denosumab.
Three weeks after surgery there were again two small areas of exposed bone in the 35 and 44 region (figure 2B), with a discharging extra-oral fistula. Pain had however slowly diminished.
Six weeks after surgery a CT scan showed no large abnormalities besides subperiosteal bone formation (figure 2D).
Sixteen weeks after the first surgery the extra-oral fistula had not disappeared and bone could be probed through it; with new abscess formation a second surgery was performed. Dur-ing exploration from area 36 to 46 a significant amount of subperiosteal bone formation was seen on both buccal and lingual surfaces. The entire region showed barely bleeding bone and greyish marrow. As much affected bone as possible was removed, up to the point of risking loss of continuity. Again, the wounds were primarily closed in layers. Histologic findings were similar to the first surgery. Cultures showed Streptococcus constellatus, Fusobacterium and Actinomyces, all sensitive to Penicillin, which was given intravenously for five days combined with metronidazole. Amoxicillin was prescribed orally for a further three months.
Figure 3 Six weeks after second surgery
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On the first postoperative day the patient developed neurologic symptoms, found to be asthe result of cerebral metastasis of the original prostate cancer (confirmed histologically). He underwent craniotomy to decompress the lesion, the patient recovered and was discharged for rehabilitation.
He was followed up in the out-patient clinic. Complaints of pain had diminished, but the extra-oral fistula and intra-oral dehiscence remained and were slowly progressive (figure 3A+B). The panoramic radiographs showed a slowly deteriorating mandible as shown in figures 3C. Eleven months after the first surgery the patient died of brain metastases from prostate cancer.
discussion
Bisphosphonates are currently the first drugs of choice when treating bone metastases from e.g. prostate or breast cancer, multiple myeloma and osteoporosis10. Prostate cancer is the most
common newly diagnosed cancer in men worldwide. Approximately 30 % of postmenopausal women in the US and Europe have osteoporosis19, and yearly nearly 2 million hip fractures occur
in the US as a result of this20. These numbers illustrate the large cohort of patients that are
potentially eligible for these drugs. A recently highlighted, and well-reported side-effect of this treatment is bisphosphonate osteonecrosis5.
A new drug in this field is Denosumab, a fully human monoclonal antibody to receptor activa-tor of NF-κB ligand (RANKL), a cytokine member of the TNF family, and the principal mediaactiva-tor of osteoclastic bone resorption10. By binding to RANKL, Denosumab prevents the activation of
RANK. This results in the inhibition of the maturation of osteoclasts and hence a decrease in their function and subsequent inhibition of osteoclast-mediated bone resorption. In trials it is delivered to the patient by subcutaneous injection several times a year with a dose varying from 60-120 mg8,9,12-14,16.
Phase I, II and III trials in both patient categories have been published demonstrating that De-nosumab has resulted in decreased levels of bone turnover markers9,15 and significant increases
in bone mineral density compared with placebo9,21. This has led to a decrease in occurrence of
non-vertebral and hip fractures8,9,15. Further studies have shown that osteoporotic patients that
have used alendronate and have switched to Denosumab have a significantly greater increase in Bone Mineral Density (BMD)11.
A potential hazard of Denosumab might be that several non-skeletal cells, including acti-vated T and B cells, also express RANK and RANKL; therefore Denosumab could have a negative effect on the immune system. Several Denosumab trials have monitored the side effects8,9,12,14,16.
A higher incidence of serious adverse effects were found in the Denosumab group compared to the placebo group (34,6 % vs. 30,6 %)9, this was not significant, although the former group
respec-tively Denosumab vs. zoledronic acid, this was not significant either12. They also showed 2%
(n=943) of osteonecrosis in the Denosumab group compared to 1% (n=945) in the zoledronic acid group, but with no significant difference. Smith et al. reported 5% (n=720) development of osteonecrosis of the jaws in patients who used Denosumab compared to zero osteonecrosis in patients receiving a placebo14. Saad et al. found a low incidence of osteonecrosis of the jaw with
Denosumab of 0,9% (n=5723 patients)16. One study reported an increased incidence of cataract
in the Denosumab group9.
In this case, there was evidence of infectious symptoms only seven months after start of Denosumab followed by invasion of the mandible and established osteomyelitis not withstand-ing repeated antibiotic and surgical treatment. Our expectation was that the mandible would ultimately loose its continuity by sequestration.
Although there is an increasing body of literature about bisphosphonate related osteone-crosis, the exact mechanism by which it is caused and develops is still unclear and debated22.
In this case report about the detrimental effects of Denosumab on the jaw bone a definite model of the working mechanism cannot be given either. However, the patient has not used any other medication aimed at influencing the bone metabolism by suppressing bone resorption. It is for this reason in our opinion there is a clear link between the drug and the disease. We feel reporting this serious, previously unknown side-effect has clinical relevance in the on-going debate on Denosumab.
conclusion
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